Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy

Abstract

Progress in the development of asymmetric Heck couplings of arenes and acyclic olefins has been limited by a tenuous understanding of the factors that dictate selectivity in migratory insertion and β-hydride elimination. On the basis of key mechanistic insight recently garnered in the exploration of selective Heck reactions, we report here an enantioselective variant that delivers β-, γ-, or δ-aryl carbonyl products from acyclic alkenol substrates. The catalyst system imparts notable regioselectivity during migratory insertion and promotes the migration of the alkene's unsaturation toward the alcohol to ultimately form the ketone product. The reaction uses aryldiazonium salts as the arene source, yields enantiomeric products from opposite starting alkene configurations, and uses a readily accessible ligand. The racemic nature of the alkenol substrate does not bias the enantioselection.

Fig. 1

(A) Classical Heck reaction with electronically biased alkenes. (B) Proposed redox-relay enantioselective Heck reactions and mechanistic analysis. (C) Proposed migration of the metal through the alkyl chain and mechanistic analysis. (D) Preliminary result. DMA indicates dimethylacetamide; dba, dibenzylidene acetone; Me, methyl group.

Fig. 2

Ligand selection and optimization protocol of the redox-relay enantioselective Heck reaction of 2a. Pr, propyl; Bu, butyl group.

Fig. 3

Scope of the enantioselective redox-relay Heck arylations of racemic allylic alcohols. Absolute configuration was determined by the synthesis of ar-(+)-juvabione (3f) and comparison to its reported optical rotation data. The balance of the entries was assigned by analogy (33, 34).

Fig. 4

Scope of the enantioselective redox-relay Heck reactions of racemic homoallylic secondary alcohols and primary alcohols.

Fig. 5

Evaluation of bis-homoallylic alcohol substrates in the enantioselective Heck reaction.